-phenyl-s-triazolo{8 4,3-a{9 {8 1,4{9 {0 benzodiazepines

ABSTRACT

This invention relates to novel 6-phenyl-s-triazolo (4,3a)(1,4)benzodiazepines embraced by the formulae   WHEREIN R is selected from the group consisting of hydrogen, lower alkyl of one through three carbon atoms, phenyl, benzyl, nitromethyl, cyanomethyl, lower alkoxymethyl having an alkoxy moiety of one through three carbon atoms;   D R A W I N G in which n is an integer of 1 through 2, R&#39;&#39; and R&#39;&#39;&#39;&#39; are each selected from the group consisting of hydrogen and alkyl of one through three carbon atoms and when combined is an alkylidene bridge of four through five carbon atoms; R1 is selected from the group consisting of hydroxy and lower acyloxy; R2, R3, R4 and R5 are selected from the group consisting of hydrogen, lower alkyl of one through three carbon atoms, halogen, nitro, cyano, trifluoromethyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, amino, lower alkanoylamino and lower dialkylamino; and a pharmacologically acceptable acid addition salt thereof. It also relates to novel processes for the preparation of the aforesaid compounds. The new products of Formulae I, II, III and IV are useful as sedatives, hypnotics, tranquilizers, muscle relaxants and anticonvulsants. Also, as feed additives for increasing growth rate and feed efficiency of livestock.

United State Hester, Jr.

[ 1 6-PHENYL-S-TRIAZOLO[4.3-A][1,4]

BENZODIAZEPINES [75] Inventor: Jackson B. Hester, Jr., Gale burg,

Mich.

[731 Assignee: The Upjohn Company, Kalamazoo,

Mich.

] Filed: July I3, I973 2]] Appl. No.: 379.093

Related U.S. Patent Documents Reissue of:

[64] Patent No.: 3,681,343

Issued: Aug. 1, 1972 Appl. No.: 142.418 Filed: May ll, I971 [52] US. CL. 260/2393 T; 260/308 R; 260/2935);

424/273; 424/267 [5 l] Int. Cl C07! 57/02 [58] Field of Search 260/2393 T, 308 R [56] References Cited UNITED STATES PATENTS 3.558.606 l/l97l Tinney 260/239.3 T

FOREIGN PATENTS OR APPLICATIONS 2,0l0 884 10/1970 Germany 260/308 R Primary E \'aminer-Henry R. .liles Assistant E.raminerRobert T. Bond Attorney. Agent. or Firm lohn T. Reynolds; William A. Hodes [57] ABSTRACT This invention relates to novel 6-phenyl-s-triazolo [4,3-a][l,4]benzodiazepines embraced by the formulae I Bl isued Aug. 5. 1975 wherein R is selected from the group consisting of h drogen, lower alkyl of one through three carbon atoms. phenyl, benzyl. nitromethyl. cyanomethyl. lower alkoxymcthyl having an alkoxy moiety of one through three carbon atoms:

in which n is an integer of 1 through 2. R and R" are each selected from the group consisting of hydrogen and alkyl of one through three carbon atoms and when combined is an ulkylidene bridge of four through five carbon atoms; R is selected from the group consisting of hydroxy and lower acyloxy: R R R and R are selected from the group consisting of hydrogen, lower alkyl of one through three carbon atoms. halogen, nitro, cyano. trifluoromethyl. lower alkoxy lower alkylthio, lower alkylsulfinyl. lower alkylsulfonyl. amino, lower alkanoylamino and lower dialkylamino; and a pharmacologically acceptable acid addition salt thereof. It also relates to novel processes for the preparation of the aforesaid compounds. The new products of Formulae I. II. III and IV are useful as sedatives, hypnotics. tranquilizers, muscle relaxants and anticonvulsants. Also. as feed additives for increasing growth rate and feed efficiency of livestock.

4 Claims. No Drawings 6-PHENYL-S-TRIAZOLO[4,3-A][ 1,4] BENZODIAZEPINES BRIEF SUMMARY OF THE INVENTION The novel 6-phenyl-s-triazolo[4,3- a][l,4]benzodiazepines of this invention are included within the generic formulae wherein R is selected from the group consisting of hydrogen, lower alkyl of one through three carbon atoms, phenyl, benzyl, nitromethyl, cyanomethyl, lower alkoxymethyl having an alkoxy moiety of one through three carbon atoms;

in which n is an integer of I through 2, R and R" are each selected from the group consisting of hydrogen and alkyl of one through three carbon atoms and when combined is an alkylidene bridge of four through five carbon atoms; amino and lower dialkyl amino; R is selected from the group consisting of hydroxy and lower acyloxy; R R R and R are selected from the group consisting of hydrogen, lower alkyl of one through three carbon atoms, halogen, nitro, cyano, trifluoromethyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, amino, lower alkanoylamino and lower dialkylamino; and a pharmacologically acceptable acid addition salt thereof.

Examples of lower alkyl include methyl, ethyl, propyl and isopropyl. Examples of Hz)n- R wherein n is an integer of 1 through 2, R and R" are each selected from the group consisting of hydrogen and alkyl of from one through three carbon atoms and when combined is an alkylidene bridge of four through five carbon atoms, include dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl, ethylaminoethyl, propylaminomethyl, propylaminoethyl, methylpropylaminomethyl, pyrrolidinomethyl and piperidinomethyl. Examples of lower acyloxy include acetoxy and propionyloxy. Examples of halogen include fluoro,

chloro, bromo and iodo. Examples of lower alkoxy include methoxy, ethoxy, propoxy and isopropoxy. Examples of lower alkyl thio include methylthio, ethylthio, propylthio and isopropylthio. Examples of lower alkylsulfinyl include methylsulfinyl, ethylsulfinyl, propylsulfinyl and isopropylsulfinyl. Examples of lower alkysulfonyl include methylsulfonyl, ethylsulfonyl, propylsulfonyl and isopropylsulfonyl. Examples of lower alkanoylamino include acetylamino and propionylamino. Examples of lower dialkylamino include dimethylamino, diethylamino, dipropylamino and diisopropylamino.

The novel 6-phenyl-s-triazolo[ 4,3

a][l,4]benzodiazepines of Formulae I, II, III and IV exist either in the non-protonated (free base) form or in the protonated (acid addition salt) form, depending on the pH of the environment. They form stable protonates, i.e., pharmacologically acceptable acid addi tion salts, on acidification of the free base form with suitable pharmacologically acceptable acids, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, acetic, propionic, palmitic, benzoic, salicylic, hexynoic, phenylbutyric, naphthoic, glycolic, succinic, nicotinic, tartaric, maleic, malic, pamoic, methanesulfonic, cyclohexanesulfonic, picric and lactic acids, and the like. Conversely, the free base of the novel compounds of Formulae I, II, III and IV can be obtained from a salt (e.g., from the hydrochloride or sulfate salt) by neutralization with a base such as sodium hydroxide, extracting with an immiscible solvent, for example chloroform, drying the extract, for example with anhydrous sodium sulfate, and removing the solvent by evaporation.

The novel compounds and processes for their production, certain of which are novel, are illustratively represented by the following sequence of formulae:

wherein R and R are lower alkyl and R, R R R R and R have the same meaning as above.

The processes for preparing the novel compounds of Formulae I, II, III and IV are described below. Process A. Starting material (A) BEL UII and II The compounds of the respective formulae wherein R. R R3. R and R have the same meaning as above, are prepared by mixing a corresponding compound of the formula wherein R, R R R and R have the same meaning as above, with a peracid.

An appropriately substituted or unsubstituted starting material of Formula A can be prepared by condensing a corresponding 1.3-dihydro-5-phenyl-2H-l ,4-benzodiazepine-Z-thione of the formula wherein R R R and R have the same meaning as above. (prepared in accordance with the procedures described in US. Pat. No. 3,422,091) with a corresponding hydrazide of the formula ii RC-NH-NH.

wherein R has the same meaning as above.

Process A involves reacting about 1 molar equivalent of a substituted or unsubstituted 6-phenyl-4H-s-triazolo [4,3-a] l ,4lbenzodiazepine (A) with about 2 molar equivalents of a peracid (also known as peroxy acid) such as peroxyacetic acid, perbenzoic acid, perphthalic acid or, preferably m-chloroperbenzoic acid, in a solvent such as a lower alkanol, chloroform, methylene chloride, etc. at from about 0 to 25 C. for from about 6 to 48 hours, to yield acorresponding 6-phenyl-4H-striazolo[4,3-a][l,4]benzodiazepine 5-oxide (II) and a corresponding 1 IbphenyI-SHJ lbH-oxazirino[3,2-d]- s-triazolo[4,3-a][ 1,4]benzodiazepine (III).

Process B Ill li -LII A compound of the formula wherein R, R R R and R have the same meaning as above.

Process B comprises heating a substituted or unsubstituted l lb-phenyl3l-l,1 lbH-oxazirinol 3.2-a1-striazolo [4.3-a][ 1,4]benzodiazepine of Formula Ill wherein R R R R and R; have the same meaning as above is prepared by condensing a corresponding compound of the Formula wherein R R R], R and R have the same meaning as above, (prepared in accordance with the procedures ol- US. Pat. Nos. 3,247,186 and $312,688) with a corresponding hydralide ol the formula wherein R has the same meaning as above.

Process is carried ottt by condensing a substituted or unsubstituted Z-OR S-phcnyIJIl l 4 benzodiazepine-4-oxide (H) with an appropriate acid hydralide in a solvent such as l-butanol or l-pentanol at from about ltll) (i to about l .18" for from about IE to about 424 hours, to yield a lrialolol 4 3-a l ,4 lbenzodialepine S-oxidc (ll). Process I) A compound of the formula corresponding o-plwnyl-4ll-swherein R R R: R and R have the same meaning as above, is prepared by steps comprising l. mixing a corresponding compound of the formula wherein R R R; R, and R have the same meaning as above with an acid anhydride of a lower alkyl carho ylie acid to yield a corresponding compound of the formula wherein R" is lower all-tyl and R. R R R and R; have the same meaning as above;

2. mixing in the cold a thus produced corresponding compound resulting from step t l with an alkali metal hydroxide to yield a corresponding compound ot the formula wherein R, R R R, and R have the same meaning as above, and

3. mixing a thus produced corresponding cotnpotmd resulting from step (I) with an alkali metal hydroxide to yield a corresponding compound ol Formula l\'.

above.

The first step of Process l) involves mixing an acid anhydride (erg. acetic anhydride or propiouie anhydride] or an acid and its anhydride tog. acetic acid and acetic.anhydritle) with a substituted or unsubstr tnted o phenyl--lll-s-lria1olol 4.3- a ll l.-l IbetUodia/epiltc 5-oxidc (ll) at from about Itltl to about 140 for from about It) to about 0 min s-trialolol 4 -a H l .4 Ilwnyodiazepine (I).

2. The next step of the process comprises hydrolyzing in the cold at the 4-position of a substituted or unsubstituted 4-acyloxy-o-phenyl-4H-s-triazolo[4,3- a][ 1.4]benzodiazepine (I) produced in step (I), for example, by slowly adding, in the course of about 1 to about hours, a dilute aqueous solution of an alkali metal hydroxide (e.g.. sodium hydroxide; to an ice cold aqueous alkanol (e.g., ethanol) solution of an aforesaid 4-acyloxy compound (I). to yield a corresponding 6- phenyl-4H-s-triazolo[4,3-a][ l,4]benzodiazepin-4-ol 3. In the final step of Process D, a substituted or unsubstituted 6-phenyl-4Hs-triazolo[4,3-a][ 1,4]benzodiazepin-4ol (I) produced in step (2) is tautomerized at the 4-position and selectively reduced at the 5- position, for example, by reacting a solution or suspension of an aforesaid 4-01 (I) with a dilute aqueous solution of an alkali metal hydroxide (e.g., sodium hydroxide or potassium hydroxide) at from about 25 C. to about 50 C. for a period of from about 1 to about 8 hours, to yield a corresponding 6-phenyl-4I-I-striazolo[4,3-a][ 1,4]benzodiazepin-4-one (IV).

Process E Starting material (C) flEEEI (4-01) A compound of the formula wherein R, R R R and R have the same meaning as above, is prepared by mixing a corresponding compound of the formula wherein R, R R R and R have the same meaning as above, with ammonia in a lower alkanol.

Process E comprises dissolving an appropriate substituted or unsubstituted 4-(2-benzoylphenyl)-4H-l,2,4- triazole-3-carboxaldehyde (C) in a solution of ammonia (preferably anhydrous) in a lower alkanol (e.g., ethanol) at a temperature of from about 0 C. to about 25 C. and allowing the reaction mixture to stand for from about 2 to about 6 hours, to yield a corresponding 6-phenyl-4H-2-triazolo[4,3 a][ l,4-benzodiazepin 4-ol (I).

An appropriately substituted or unsubstituted starting material of Formula C can be prepared by steps comprising 1. heating under nitrogen a mixture of a 2-halo-4- phenylquinoline (prepared as in J. Heterocyclic Chem. 3. 359) and hydrazine hydrate, to yield a 2hydroa2ino- 4-phenylquinoline;

2. refluxing an equimolar mixture of a 4-phenylquinoline prepared in step (1 and a trialkyl orthoacetate, under nitrogen. in a solvent (e.g., xylene), to yield a corresponding S-phenyl-s-tria2olo[4,3-a]quinoline;

3. reacting an s-tri'azo]o[4,3-a]quinoline prepared in step (2) (in acetone) in the cold with a mixture of ruthenium dioxide and sodium periodate (in water), to yield a corresponding 1,2,4-triazol-4- yl)benzophenone and a corresponding 4-(2- benzoylphenyl)-4H-1,2,4-triazole-3-carboxaldehyde (C). (The preparation of a specific starting material of Formula C, namely, 4-(2-benzoyl-4-chlorophenyl)-5- methyl-4H-l,2,4-triazole-3-carboxaldehyde, is described in Parts A, B and C of Example 6, below.)

All of the novel compounds included with Formulae I, II, III and IV and the starting materials (A, B and C) therefor of the flow-sheet, above, can be isolated from their respective reaction mixtures by conventional means, for example, when a water-miscible solvent is used, by pouring the reaction mixture into water and separating the resulting precipitate by filtration or by extraction with water-immiscible solvents. Additional purification of the products can be accomplished by conventional means, for example, by elution chromatography from an adsorbent column with a suitable solvent such as acetone, ethyl acetate, ether, methylene chloride and Skellysolve B (hexanes), mixtures and combinations of these solvents; also by gradient elution chromatography from an adsorbent column with a suitable mixture of solvents, such as, methylene chloride Skellysolve B, acetone-Skellysolve B, and the like.

a The novel compounds of Formulae I, II, III and IV and the pharmacologically acceptable acid addition salts thereof have sedative, hypnotic, anticonvulsant, tranquilizing and muscle relaxant effects in mammals and birds. Also, as feed additives for increasing growth rate and feed efficiency of livestock.

Sedative effects of the compound of this invention are shown by the following tests in mice:

Chimney test: [Med. Exp. 4, (1961 )1: The test determines the ability of mice to back up and out of a vertical glass cylinder within 30 seconds. At the effective dosage, 50 percent of the mice failed doing it.

Dish test: Mice in Petri dishes (10 cm. diameter, 5 cm. high, partially embedded in wood shavings), climb out in a very short time, when not treated. Mice remaining in the dish for more than 3 minutes indicates tranquilization. ED equals the dose or test compound at which 50 percent of the mice remain in the dish.

Pedestal test: The untreated mouse leaves a standard pedestal in less than a minute to climb back to the floor of the standard mouse box. Tranquilized mice will stay on the pedestal for more than 1 minute.

Nicotine antagonism test: Mice in a group of six are injected with the test compound. Thirty minutes later the mice including control (untreated) mice are injected with nicotine salicylate (2 mg./kg.).

The control mice show overstimulation, i.e., (1)

running convulsions followed by (2) tonic extensor fits; followed by (3) death.

Antagonism to strychnine (as sulfate): The test consists in orally administering into groups of six mice COMPOUND Ch D P Ni 8-chlorol-methyl6- phenyl-4H-striazolo [4.3a][ 1,4]benzodiazepin -4-ol (I) 4-acetoxy-8 chlor0- l-methyl-6-phenyl- 4H-s-triazolo[4,3-a] [l,4]benzodiazepine (I) 8-chlorol-methyl- 6-phenyl-4H-striazolo[4,3-a][ 1,4]- benzodiazepine oxide (II) 5 lO-chloro--methyl-l 1bphenyl-3H.l lbl-I- oxazirino[3,2-d]-striazolo[4,3-a][ L4] benzodiazepine (Ill) 8-chloro-S -dihydrol methyl-6-phenyl-4H-s triazolo[4,3-a][ [,4] benzodiazepin-4-one (IV) Ch chimney lest D dish test P pedestal test Ni nicotine antagonism (3) test The pharmaceutical forms contemplated by this invention include pharmaceutical compositions suited for oral, parenteral and rectal use, e.g., tablets, powder packets, cachets, dragees, capsules, solutions, suspensions, sterile injectable forms, suppositories, bougies, and the like. Suitable diluents or carriers such as carbohydrates (lactose), proteins, lipids, calcium phosphate, cornstarch, stearic acid, methylcellulose and the like can be used as carriers or for coating purposes. Oil, e.g., coconut oil, sesame oil, safflower oil, cottonseed oil, peanut oil can be used for preparing solutions or suspensions of the active drug. sweetening, coloring and flavoring agents can be added.

For mammals and birds food premixes, with starch, oatmeal, dried fishmeat, fishmeal, flour and the like can be prepared.

As tranquilizers the compounds of Formulae I, II, III and IV can be used in dosages of 0.1 mg. to 20.0 mg./kg. in oral or injectable preparations as described above, to alleviate tension and anxiety in mammals, or birds, such as e.g., occurs when animals are travelling.

DETAILED DESCRIPTION OF THE INVENTION The following preparation and examples are illustrative of the processes and products of the present invention, but are not to be construed as limiting. Preparation 1 8-chlorol -methyl-6-phenyl-4H-striazolo-[4,3-a][ 1,4]benzodiazepine (A) A mixture of 5 g. of 7-chloro-1,3-dihydro-5-phenyl- 2I-I-l,4-benzodiazepine-2-thione (prepared as in US. Pat. No. 3,422,091) and 3.89 g. of acethydrazide in 175 ml. of absolute ethanol is heated for about 24 hours. The reaction mixture is then cooled and concentrated to give a residue. The residue is treated witl" water and the aqueous suspension filtered. The solids remaining on the filter are dissolved in methylene chloride, the solution dried over anhydrous potassium carbonate, evaporated to dryness and then recrystallized from ethyl acetate. The material thus obtained is melted under nitrogen in an oil bath maintained at about 250 C., cooled and recrystallized from ethyl 21cetate to give S-chloro-l-methyl-6-phenyl-4H-striazolo[4,3-a][l,4]-benzodiazepine (A) having a melting point of 227.5 C. to 228.5 C.

Following the procedure of Preparation 1 but substituting another known representative 2H-l,4-bcnzodiazepine-Z-thione starting material (prepared as in US. Pat. No. 3,422,091) and reacting it with acethydrazide or another known representative hydrazide, such as l. l,3-dihydro-5-phenyl-2H-l ,4-benzodiazepine-2- thione and acethydrazide,

2. 6-chlorol ,3-dihydro-5-(o-bromophenyl)-2H- l ,4

benzodiazepine-Z-thione and acethydrazide,

3. 7-chloro-l ,3-dihydro-5-( 2,4-dichlorophenyl )-2H- l,4-benzodiazepine-2-thione and acethydrazide. 4. 8-bromol ,3-dihydro-5-( 3,4-climethylphenyl )-2H- l,4-benzodiazepine-2-thione and acethydrazide. 5. 7-bromo-1,3-dihydro-5-(2-methyl-4 methoxyphenyl )-2H- 1 ,4-benzodiazepine-Z-thione and acethydrazide,

6. l,3-dihydro-7-methyl-5-(3-methyl-5- chlorophenyl)-2I-I-1,4-benzodiazepine-2-thione and acethydrazide,

7. l ,3-dihydro-7-fluoro-9-nitro-5-pheny1-2H- l ,4-

benzodiazepine-Z-thione and acethydrazide,

8. l,3-dihydro-5-[p-(propionylamino )phenyl ]-2H- 1,4-benzodiazepine-2-thione and acethydrazide,

9. 8-cyano-l ,3-dihydro-5-[p- (trifluoromethyl )phenyl ]-2H- I ,4-benzodiazepine- 2-thione and butyric acid hydrazide,

l0. 7,9-dichloro-l ,3-dihydro-5-(o-chlorophenyl 2H-1,4-benzodiazepine-2-thione and isobutyric acid hydrazide,

1 1. 7-bromo-1,3-dihydro-8-ethylthio-5-(o-fluorophenyl )-2H- 1 ,4-benzodiazepine-2-thione and formic acid hydrazide,

l2. l,3-dihydro-9-diisopropylamino-7-ethyl-5-[m- (propylsulfonyl)phenyl]-2H-1 ,4-benzodiazepine- 2-thione and formic acid hydrazide,

l3. l,3-dihydro-7-fluoro-5-( 3-methyl-5 chlorophenyl)-2I-I-1,4-benzodiazepine-Z-thione and formic acid hydrazide,

14. 7-bromol ,3-dihydro-5-phenyl-2l-I- l ,4-benzodiazepine-2-thione and benzoic acid hydrazide,

l5. 7-chloro-l ,3-dihydro-5-(m-chlorophenyl)-2H- l,4-benzodiazepine-Z-thione and benzoic acid hydrazide,

l6. 7-bromol ,B-dihydro-S-[o- (ethylsulfinyl)phenyl]-8-methoxy-2I-l-1,4-benzodiazepine-Z-thione and phenylacetic acid hydraethyl-ZI-I-l,4-benzodiazepine-Z-thione and cyano- [4.3-a][1,4]benzodia2epine (A),

l 8. 8-bromo-6-(o-bromophenyl l -cyanomethyl-9- ethyl-4H-s-triazolo[4.3-a][ 1,4 ]benzodiazepine 19. 8,l-bis(dipropylamino)- l-methoxymethyl-6-(onitrophe nyl)-4H-s-tria2olo[4,3-

a][ l ,4]benzodiazepine (A),

20. l0-trifluoromethyl-7,9-diethyl-l-ethoxymethyl- 6-(o-nitrophcnyl)4H-s-triazolo[4,3- a][ 1,4]benzodiazepine (A),

21. 6-(o-cyanophenyl)- l -(dimethylamino)rnethyI-7- nitro-4I-l-s-triazolo[4,3a][ 1,4]benzodiazepine (A) 22. l-( diethylamino )methyl-6-( 2,6-difiuorophenyl 8-trifluoromethyl-4H-s-triazolo[4,3-

a][ 1,4]benzodiazepine (A),

23. 8-ch1oro-9-methylmercaptol methylpropylamino )-ethyll0-nitro-6-phenyl-4H-striazolo[4,3-a][ 1,4]benzodiazepine (A),

24. .1 aminomethyl-8,9-dibromo-6-(methoxyphenyl)-4H-s-triazolo[4,3-

a][ 1,4]benzodiazepine (A),

25. 8-chloro-6-[(o-trifiuoromethyDphenyl]-l- (ethylamino)methyl-9-nitro-4H-s-triazolo[4,3-

a][ 1,4]benzodiazepine (A),

26. l-(diethylamino)methyl-7-ethylthio-6-(pfluorophenyl)-4H-s-triazolo[4,3- a][ l ,4]benzodiazepine (A),

27. S-trifluorornethyl-l-(ethylmethylamino)methyl- 9-methyl-6-(o-nitrophenyl)-4H-s-triazolo[4,3- a][ 1,4]benzodiazepine (A),

28. 8-ch1oro-6-(3,5-dinitropheny1)-lpyrrolidinomethyl-4H-s-triazolo[4,3- a][ l ,4]benzodiazepine (A),

29, 9-bromo-6-( 2-chloro-4-fluorophenyl)-8-ethyll pyrrolidinomethyl-4H-s-triazolo[4,3- a][1,4]benzodiazepine (A),

30. 6-( 2ethyl-4-propylphenyl l -piperidinomethyl- 8,9, l 0-trimethyl-4H-s-triazolo[4,3-

a][ l,4]benzodiazepine (A),

31. 8-dimethylaminol -ethyl-6-phenyl-4H-s-triazolo- [4,3-a][1,4]benzodiazepine (A),

32. 7,9-diethyl-6-(m-ethylphenyl)-7-nitro- 1- nitromethy]-4H-s-triazolo[4,3- a][1,4]benzodiazepine (A),

33. 1-cyanomethyl-8,9-dibromo-6-phenyl-4H-striazolo-[4,3-a][1,4]benzodiazepine (A),

34. l-( diethylamino )methyl-7,8-dimethyl-6-(opropylphenyl )-9-trifluoromethyl-4H-striazolo[4,3-a][ 1,4]-benzodiazepine (A),

35. 9-trifluoromethyl-8-ethyl-6-(m-iodophenyl l- (methylamino)methyl-4H-s-triazolo[4,3- a][1,4]benzodiazepine (A),

36. 8-bromol -(dipropylamino)methyl-9-propoxy-6- (p-propoxyphenyl)-4H-s-triazolo[4,3-

a][ l ,4]benzodiazepine (A),

37. 10-acetylaminol -ethyl-6-phenyl-4H-s-triazolo- [4,3-a][ 1,4]benzodiazepine (A),

38. 8,9-dichlorol ,6-diphenyll O-trifluoromethyl- 4H-s-triazolo[4,3-a][ 1,4]benzodiazepine (A),

39. l-benzyl-9-bromo-6-(m-fluorophenyl )-8methyl- 4H-s-triazolo[4,3-a][1,4]benzodiazepine (A),

40. 7,10-dichloro-6-(p-isopropylphenyl)-lnitromethyl-4H-s-triazolo[4,3-

a][ 1 ,4]benzodiazepine (A),

4!. l-cyanomethyl-8,9-diethyl-6-( m-ethylphenyl 4H-s-triazolo[4,3-a][ 1,4]benzodiazepine (A),

42. 8-bromo-9ethyll -propoxymethyl-6-( p-propoxyphenyl )-4H-s-triaZolo[4,3-a][ 1.4]benzodiazcpinc (A).

43. 9-chloro-l-(methylethylamino)methyl-7-propyl- 6-(o-propylphenyl)-4H-s-triazolo[4,3 a][],41benzodiazepine (A),

44. l-aminomethyl-8,9-dibr0mo-7-ethyl-6-[m- (ethyl-sulfinyl)phenyl]-4H-s-triazolo[4,3

a][ l ,4]benzodlazepine (A),

45. 9-bromo-8-methyl-6-phenyl-l-piperidinomethyl- 4H-s-triazolo[4.3al[l .4Ibenz0diazepine (A).

46. 8-ethyl-9fluorol propoxymethyl-6-( opropoxyphenyl)-4H s-tria2olo[4,3-

a][ l ,4]benzodiazepine (A),

47. 10chlorol -isopropoxylmethyl-6-phenyl-4H-striazolo[4,3-a][1,4]benzodiazepine (A),

48 8-chloro-6-(2,4-difluorophenyl)-l-ethoxymethyl- 9-ethyl-4l-I-s-triazolo[4,3-a][ 1,4]benz0diazepine (A),

49. 9-bromo-6-[o-(ethylsulfonyl)phenyl]-8-propoxy- 4H-s-triazolo[4,'3-a][ 1,4]benz0diazepine (A),

50. lO-acetylamino-8,9-dichloro-7-ethyl-6-(m-nitrophenyl l -phenyl-4H-s-triazolo[4,3-

a][ l ,4]benzodiazepine (A), etc] Example 1 A. l0-chloro-6-methyl-l lb-phenyl-3H,1 lbH- oxazirino[3,2-d]-s-triazolo[4,3-a][1,4]- benzodiazepine (III) B. 8-chloro-l-methyl-6-phenyl-4H-s triazolo-[4,3- a][l,4]benzodiazepine 5-oxide (II) I A. lO-chloro-6-methyl-l lb-phenyl-3I-Ll lbH- oxazirino-[3,2-d]-s-triazolo[4,3-

a][ l,4]benzodiazepine (III) A stirred solution of l g. (0.00324 mole) of 8-chloro- 1-methyl-6-phenyl-4I-I-s-triazolo 4,3 a][1,4]benzodiazepine (A), (obtained as in Preparation I) in absolute ethanol is cooled in an ice bath and mixed with 1.12 g. (0.00648 mole) of mchloroperbenzoic acid. The mixture is kept in the ice bath for about 6 hours and then at room temperature for about 18 hours. It is then concentrated under vacuum; the residue is suspended in cold, dilute potassium carbonate solution and extracted with methylene chloride. The extract is washed with water, dried with potassium carbonate, concentrated under vacuum, chromatographed on a 100 g. column of silica gel and 50 m1. fractions collected. Fractions 1 through 48 are eluted with a mixture of 5 percent methanol and 95 percent ethyl acetate and fractions 49 through with 10 percent methanol percent ethyl acetate. The first compound is eluted in fractions 18 through 28 and crystallized from ethyl acetate to give 0.334 g. of 10- chloro-fi-methyl-l lb-phenyl-3H,l lbH-oxazirino[3,2- d]-s-triazolo[4,3-a][ l,4]benzodiazepine (Ill), melting at [695 to C. (with decomposition) and 0.031 g. of the same compound melting at l68.5 to l69.5 C. (with decomposition). The analytical sample has a melting point of 167 to l67.5 C., ultraviolet (ethanol) end absorption with inflections at 235 my. (Fl 6,700), 263 mp. (F939), 269 my. (F776), 275 mp. (F594) and 28l mu (F523). The infrared, nuclear magnetic resonance and mass spectra support the proposed structure.

Anal. Calcd. for C H CIINMO: C. 62.88; H. 4.03:

C]. 10.92; N. 17.25. Found: C. 62.95: H. 3.94: CL. H.051 N. 17.09.

The second compound is eluted from the column in 9. 7,9-dichlorol .o-diphenyll O-trifluoromethy1-4H- s-triazolol4,3a][1,4]benzodiazepine 5-oxide (II),

10. l-cyanomethyl-Q,l-diethyl-6-(o-propylphenyl)- 4H-s-triazolo[4.3-a]l1.4]benzodiazepine S-oxide 1 1. 8-bromo-7-methyl-6-(m-propoxyphenyl)-4H-striazolo[4,3-a][ l,4]benzodiazepine S-oxide (II),

12. 8,9-difluoro-1-phenyl6-(o-methylphenyl)- l0- trifluoromethyl4H-s-triazolo[4,3- a][1,4]benzodiazepine 5-oxide (ll),

13. lO-chloro-8-ethyl-6-(o-ethylphenyl)-lpiperidinomethyl-4H-s-trizolo[4,3-

a][ 1,4]benzodiazepine 5oxide (ll),

14. 8-bromo 6-(2,4-difluorophenyl)-1- ethoxymethyl-9-ethyl-4H-s-triazolo[4,3 a][ l .4]benzodiazepine 5-oxide (II),

15. 9-trifluoromethyl-7-ethyl-6-(p-fluorophenyl)-l- (methylamino)methyl-4H-s-triazolo[4,3- a][1,4]benzodiazepine (ll), etc.

Example 4 4.acetoxy-8-chloro-1-methyl-6-phenyl-4H- s-triazolo[4,3-a][ 1,4]benzodiazepine (I) A stirred mixture of 2.39 g. (0.00734 mole) of 8- chlorol -methyl-6-phenyl-4H-s-triazolo[4,3- a][ l ,4]benzodiazepine 5-oxide (II) (prepared as in Example l or 3), 11.8 ml. of acetic anhydride and 7 ml. of acetic acid is warmed on a steam bath, under nitrogen, for about 30 minutes and concentrated under vacuum. The residue is suspended in water, neutralized to about pH 7 with dilute sodium carbonate solution and extracted with methylene chloride. The extract is dried with potassium carbonate and concentrated. Crystallization of the residue from ethyl acetate gives 0.96 g. (36 percent yield) of 4-acetoxy-8-chloro-l-methyl-6- phenyl-4H-s-triazolo[4,3-a][ 1,4]benzodiazepine (I), having a melting point of 233.5 to 235 C. A second crop of 0.55 g. melting at 225 to 227 C. is also obtained. The analytical sample is crystallized from a mixture of ethyl acetate and Skellysolve B (hexanes) and has a melting point of 235.5 to 236.5 C.; ultraviolet (ethanol) )tmax. 223 m (F38,300), inflections at 248 my. (6 13.750). 270 my. (e=6.850). 290 mp. (e==4,100); infrared (Nujol) absorption at 1730 cm (C=0). The nuclear magnetic resonance spectrum of the compound supports its proposed structure.

Anal. Calcd. for C I-I CIN O C, 62.21; H, 4.12; CI,

Found: C, 62.27; H, 4.21; CI, 9.38; N, 14.79.

Following the procedure of Example 4 but substitut-- ing another 4H-s-triazolo[4,3-a][ 1,4]benzodiazepine 5-oxide (11), such as l. 1-ethyl-6-phenyl-4H-s-triaz0lo[4,3-

a][ 1,4]benzodiazepine 5-oxide (II),

2. 8-bromo-6-(2,4-dich1orophenyl)-1-methyl4H-striazolo[4,3-a][ 1,4]benzodiazepine 5-oxide (II),

3. 8-chloro-6-( p-fluorophenyl l -isopropyl-4H-striazolo[4,3-a][1,4]benzodiazepine 5-oxide (II),

4. 1-benzyl-7-chloro-6-[p-(methylsulfinyl )phenyl 4H-s-triazolo[4,3-a][ 1,4]benzodiazepine S-oxide 5. 9,10 -dimethyl-8-fluoro-6-(o-chlorophenyl)-4H-striazolo[4,3-a][ 1,4]benzodiazepine 5-oxide (ll),

6. 7,8-bis(diethylamino)- l -ethoxymethyl-6-( mmethoxyphenyl )-4l-I-s-triazol0 4,3- a][1,4]benzodiazepine S-oxide (II),

7. 1-aminomethyl-7,8-dichloro-6-[o- (trifluoromethyl )-phenyl ]-4H-s-tn'azolo 4,3 a][1,4]benzodiazepine 5 oxide (II).

8. 9-trifluoromethyl-7-ethyl-6-( p-methylphcnyl 1 O Lil -fluoromcthyl4H-s triazolo[4.3- a][l.4]benzodiazepine 5-oxide (ll),

9. 9-chloro-8ethyl-6-phenyl- 1 -pyrrolidinomethyl- 4H-s-triazolo[4,3-a1[1,4]benzodiazcpine i oxidc 10. 10'acetylamino-7,8-dibromo-9-methyl-6-(mnitrophenyl )-4H-s-triazolo[4.3- a][1,4]benzodiazepine 5-oxide (II), etc..

yields, respectively,

1. 4-acetoxyl -ethyl-6-phenyl-4H-s-triazolo[ 4.3

a][ 1,4]benzodiazepine (l),

2. 4-acetoxy-8-bromo6-(2,4-dichlorophenyl l methyl-4H-s-triazolo[4,3-21][ 1,4]benzodiazepine 3 4-acetoxy8chloro-6-(p-fluorophenyl)-l isopropyl-4H-s-triazolo[4,3- a][1,4]benzodiazepine (l),

4. 4-acetoxy- 1 -benzyl-7-chloro-6-[p- (methylsulfinyl)-phenyl]-4I-I-s-triazolo[4,3-

a][ 1,4]benzodiazepine (I),

5. 4-acetoxy-9, 1 0-dimethyl-8-fluoro-6-(ochlorophenyl )-4H-s-triazolo I 4,3- a][1,4]benzodiazepine (I),

6. 4-acetoxy-7,8-bis(diethylamino)-l-ethoxymethyl- 6-(m-methoxyphenyl)-4l-I-2-triazolo[4.3-

a][ 1,4]benzodiazepine (I),

7. 4-acetoxy-1-aminomethyl-7,8-dichloro-6-[o- (trifluoromethyl)phenyl] 4H-s-triazolo[4,3-

a][ l ,4]benzodiazepine (I),

8. 4-acetoxy-9trifluoromethyl7 ethyl-6-(p-methylphenyl l O-trifluoromethyl-4l-I-s-triazolo 4,3-

a][ l ,4]benzodiazepine (l),

9. 4-acetoxy-9-chloro-8-ethyl-6-phenyl-1 pyrr0lidin0methyl-4I-I-2-triazolo[4.3- a][ 1,4]benzodiazepine (I),

10. 4-acetoxylO-acetylaminoJ,8-dibromo-9- methyl- 6-(m-nitrophenyl)-4H-s-triazolo[4.3- a][ 1,4]benzodiazepine (1), etc.

Following the procedures of the immediately preceding paragraph and of Example 4, but substituting propionic anhydride and propionic acid for the acetic anhydride and acetic acid employed therein, gives the corresponding 4-propionyloxy counterparts of Formula 1. Likewise, the substitution of another organic carboxylic acid (preferably a hydrocarbon carboxylic acid containing from one through three carbon atoms) and the anhydride derived therefrom yields the corresponding 4-acyloxy compound (I),

Example 5 8-chloro-l-methyl 6-phenyl-4H-s-triazolo- [4,3-a]]1,4]benzodiazepin-4-ol (I) A stirred suspension of 2.6 g. of 4-acetoxy-8-chlorol-methyl-6-phenyl-4H-s-triazolo[4,3- a][ 1,4]benzodiazepine (I), (prepared as in Example 4) in 130 ml. of percent ethanol is cooled in an ice bath, under nitrogen, and treated dropwise, during a period of 1 hour and 50 minutes, with 7.28 ml. of a IN sodium hydroxide solution in 26 ml. of water. The solution is kept in the ice bath for an additional hour. poured into ice water, treated with a small volume 01 brine and extracted with chloroform. The extract is washed with brine, dried with magnesium sulfate and concentrated under vacuum. The residue is crystallized from a mixture of chloroform and ethanol to give 2.2 g. of the ethanol solvate of 8-chloro-l-methyl-6- phenyl-4H-s-triazolo-l4,3-a][ 1,4]benzodiazepin-4-o1 (I), melting at 242 C. (with decomposition). The analytical sample has a melting point of 245.5 to 246.5

C.. ultraviolet absorption (ethanol) Amax. 223 mu ($34,150), 246 mu (inflection, e==l3,200), 266 mu (inflection. 6 61. 275 mu (inflection. 6 4.900). 285 mp. (inflection, $3,650), 298 mp. (inflection, c=2,050).

Anal. Calcd. for C H C1N,O.C H OH: C, 61.53; H,

5.16; Cl, 9.56; N, 15.11. Found: C. 61.68; H, 5,32; Cl, 9.71; N,

C H OH. 9.25.

Heating the solvate in a desiccator at about 70 C. at mm. Hg for about 72 hours gives pure 8-chloro-1- methyl-6-phenyl-4H-s-triazolol 4,3-a][ 1,4]benzodiazepin-4-ol (1).

Following the procedure of Example 5 but substituting another 4-acyloxy-4H-s-triazolo[4,3- a][1,4]benzodiazepine (1), such as ethyl-4H-striazo10[4.3a][1.4lbenzodiazepine (l). 4 acetoxyl ,8-dimethyl-6( 3-ethyl-4 methoxyphenyl)-4H-s-triazo1o[4,3-

a][ 1,4]benzodiazepine (I),

3. 4-acetoxy-9-cyano l -propyl-6- p- (trifluoromethyl)-phenyl]-4H-s-triazolo[4,3-

a][ 1,4]benzodiazepine (I),

. 4propionyloxyl0-trifluoromethyll (dimethylamino )methy1-6-(m-propoxyphenyl 4H-s-triazolo[4,3-a][ l,4]-benzodiazepine (I),

5. 4-propionyloxy-8-[trifluoromethyl- 1- piperidinomethyl-6-(p-nitrophenyl)-4I-I-striazolo[4,3-a][ 1,4]benzodiazepine (I),

. 4-propionyloxy-9-(methy1mercapto)- l- (methylpropylamino)-ethyl-10-nitro-6-[o- (isopropylsulfonyl )phenyl]-4H-s-triazolo[4,3- a][1,4]benzodiazepine (1), etc.,

yields respectively,

1. 8-chloro-6-( 2,6-difluorophenyl 1 -ethyl-4H-striazo1o[4,3-a][ 1,4]benzodiazepin-4-ol (I),

1 ,8-dimethyl-6-( 3-ethyl-4-methoxyphenyl )-4H-striazolo[4,3-a][ 1,4]benzodiazepin-4-ol (I),

3. 9-cyanol -propyl-6[p-(trifluoromethyl )phenyl]- 4H-s-triazolo[4.3-a][1 ,4lbenzodiazepin-4-ol (l).

10 trifl uoromethyll -(dimethylamino)methyl-6- (mpropoxyphenyl)-4H-s-triazolo[4,3-a][ 1,4]benzodiazepin-4-ol (I),

5. 8trifluoromethyl- 1-piperidinomethyl-6-( pnitrophenyl )-4H-s-triazolo[4,3-a][ 1,4]benzodiazepin-4-ol (I),

6. 9-(methy1mercapto l (methylpropylamino)ethyl-10-nitro-6-[oisopropylsulfonyl )phenyl -4I-l-s-triazolo- [4 ,3 a][ 1,4]benzodiazepin-4-ol (I), etc.

Example 6 8-chloro-1methyl-6-phenyl-4I-I-s-triazolo- [4,3-a][ l ,41benzodiazepin-4-ol (I) A. 6-chloro-2-hydrazino-4-phenylquinoline A stirred mixture of 2.7 g. (0.01 mole) of 2.6dichloro-4-phenylquinoline (prepared as in J. Heterocyclic Chem. 3, 359) and 6.8 g. of hydrazine hydrate is refluxed under nitrogen for about 1 hour and concentrated in vacuo. The residue is suspended in warm water, and the solid collected by filtration, dried and recrystallized from ethyl acetate-Skellysolve B (hexanes) to give 1.81 g. (67 percent yield) of 6- chloro-2-hydrazino-4-phenylquinoline of melting point 156.5 to 157.5 C.

Anal. Calcd. for C H C1N C, 66.79; H, 4.49; Cl,

13.15; N, 15.58. Found: C, 67.15; H, 4.65; Cl, 13.19; N, 15.32.

24 B. 7chlorol -methyl-5-pheny1-s-triazo |o[4,341 lquinoline A stirred mixture of 1.4 g. (0.0052 mole) of 6-ch1oro- 2-hydrazino4-phenylquinoline (prepared as in Part A, above), 0.925 g. (0.0057 mole) of triethyl orthoacetate and 100 ml. of xylene is refluxed, under nitrogen, for about 2 hours, 40 minutes. During this period the ethanol formed in the reaction is removed by distillation through a short, glass helix-packed column. The mixture is concentrated to dryness in vacuo and the residue is crystallized from methanol-ethyl acetate to give: 1 .02 g. of 7-chloro-l-methyl-5-phenyl-s-triazolo[4,3- a]quinoline of melting point 2535 to 255 C. and 0.26 g. of melting point 253.5 to 255 C. (83.9 percent yield). The analytical sample is crystallized from methylene chloride:methanol and has a melting point of 252.5" to 253.5 C.

Anal. Calcd. for C H ClN z C, 69.50; H, 4.12; Cl, 12.07; N, 14.31. Found: C, 69.39; H, 4.02; Cl, 12.10; N, 14.49.

C. 5'chloro-2-( 3-methyl-4H- l ,2,4-triazol-4-yl benzophenone (D) and 4-(2-benzoy1-4-chlorophenyl)- 5-methyl4H-1,2,4-triazole-3-carboxaldehyde (C) A stirred suspension of 2.94 g. (0.01 mole) of 7- chlorol-methyl-5-phenyl-s-triazolo[4,3-a1quinoline (prepared as in Part B, above) and 200 ml. of acetone is cooled in an ice bath and treated, dropwise, during a period of about 15 minutes, with a solution prepared from 200 mg. of ruthenium dioxide, 4 g. of sodium periodate and 35 ml. of water. A slight exothermic reaction is noted and the mixture becomes dark. After about 10 minutes, 29 m1. of solution containing 12 g. of sodium periodate in m1. of water is added during about 10 minutes. This mixture is stirred for about 2 hours and then the 41 m1. of remaining sodium periodate solution is added during the next 3 hours. The mixture is allowed to remain at 4 for 18 hours and is concentrated in vacuo to remove acetone. The resulting aqueous mixture is extracted with methylene chloride. The extract is washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue is chrornatographed on 150 g. of silica gel with 2 percent methanol-98 percent chloroform; 60 ml. fractions are collected. Recovered starting material is eluted in fractions 1 114 and crystallized from methanolmethylene chloride to give 0.069 g. of melting point 251.5 to 253.5 C. A mixture of the two products (C and D) is eluted in fractions 15-39. Crystallization of this mixture from ethyl acetate gives 618 mg. (20.8 percent) of 5-chloro-2-(3-methyl- 4H- 1 ,2,4-triazo1-4- yl)benzophenone (D) of melting point 165.5 to 168 C. Crystallization of the mother liquor from methanol gives 0.126 g., melting point 108-112 and 0.588 g. of melting point 101 .5 to l05.5 C. (decomposition) (19.9 percent yield) of a methanol solvate of 4-(2- benzoyl-4-chlorophenyl )-5-methyl-4I-I- l ,2,4-triazole- 3-carboxaldehyde (C). The analytical sample has a melting point of to 101.5 C.

Anal. Calcd. for C I-1 019 0 C, 62.68;I-1, 3.71; CI, 10.89; N, 12.90. Found: C, 59.37; H, 4.89; Cl, 9.75; N, 11.30; MeOI-I, 9.34%; H 0, 040%. Corrected for MeOH and H 0: C. 61.90; H. 4.06; Cl. 10.80; N. 12.52.

Heating the solvate in a desiccator at 70 C. at 15 mm. Hg for 72 hours gives pure 4-(2-benzoyl-4- chlorophenyl) 5-methyl-4H-1,2,4-triazole-3 carboxaldehyde.

D. 8-chloro-1-methy1-6-phenyl-4H-s-triazolo[4,3-a1- [1,4]benzodiazepin-4-ol (I) To 25 ml. of 95 percent ethanol (previously saturated with ammonia at room temperature) 0326 g. (0.001 mole) of 4-(2-benz0yl-4-chlorophenyl)-5-methyl4H- 1.2.4-triazole-3-carboxaldehyde (C) (prepared as in Part C, above) is added. The resulting mixture is stirred for about hours and then concentrated under vacuum at about to C. The residue is crystallized from ethanol to give 0.189 g. of the ethanol solvate of 8- chlorol -methy1-6-phenyl-4I-I-s-triazolo[4,3- a][ l,4]benzodiazepin-4-ol (I), having a melting point of 238.5 to 239 C. (with decomposition). This material is identical to an authentic sample by infrared, ultraviolet and nuclear magnetic resonance spectroscopic comparison.

Heating the solvate in a desiccator at 70 C. for about 72 hours gives pure 8-chloro-l-methyl-6-phenyl-4H-striazolo[4,3-a][1,4]benzodiazepin-4-ol (I).

Following the procedure of Example 6, Part D, but substituting another 4H-1 ,2,4-triazole-3- carboxaldehyde, such as l. 4-( 2-benz0yl-4,6-dibromophenyl )-5-ethyl-4H- 1,2,4-triazole-3-carboxaldehyde (C),

2. 4-(2-benzoyl-3-methylphenyl)-5-propyl-4H-1,2,4-

triazole-3-carboxaldehyde (C),

3. 4-(2-benzoyl-3-chloro-5-methylphenyl)S-phenyl- 4I-I- I ,2,4-triazole-3-carboxaldehyde (C),

4. 4-[2-(o-bromobenzoyl)-5-ethylphenyl]-5-aminomethyl-4I-I- 1 ,2,4-triazole-3-carboxaldehyde (C),

5. 4( 2-benzoyl-4-flu0ro-6-ethylphenyl )-5-benzyl- 4I-I- l ,2,4-triazole-3-carboxaldehyde (C), etc.,

yields, respectively,

I 8, l O-dibromol-ethyl-6phenyl-4I-I-s-triazolo- [4,3-a][1,4]benzodiazepin-4-ol (I),

2. 7-methyll -propyl-6-phenyl-4H-s-triazolo[ 4,3-a]

[1,4]benzodiazepin-4-ol (I),

3. 7-chloro-1 ,6-diphenyl-9-methyl-4H-s-triazo1o- [4,3-a][ 1,4]benzodiazepin-4-ol (I),

4. I-aminomethyl-6-(o-bromophenyl)-9-ethyl-4H-striazolo[4,3-a][1,4]benzodiazepin-4-ol (I),

triazolo-[4,3-a][ 1,4]benzodiazepin-4-ol (I), etc.

Example 7 8-chloro-5,6-dihydro-1-methyl-6-phenyl- 4H-s-triazolo[4,3-a] 1,4]benzodiazepin-4-one (IV) A stirred suspension of 0.341 g. (0.001 mole) of 8- chloro- 1-methyl-6-phenyl-4H-s-triazolo[4,3- a][l,4]benzodiazepin-4-ol (I) in 25 ml. of 95 percent ethanol is mixed with 1 ml. of IN sodium hydroxide solution, at room temperature, under nitrogen, for about 18 hours and then concentrated under vacuum. The residue is mixed with water and extracted with chloroform. The extract is dried with magnesium sulfate and concentrated. The resulting residue is crystallized from a mixture of ethanol and chloroform to give 0.02 g. of 8-chloro-5 ,6-dihydro- 1 -methyl-6-phenyl-4H-striazolo[4,3-a][ l,4]benzodia zepin-4-one (IV) having a Anal. Calcd. for C H CIN O: C, 62.87; H. 4.03: CI, 10.92; N. 17.25. Found: C, 62.75; 62.58: H. 4.35: 4.lO; Cl, l 1.08; N, 17.14.

Following the procedure of Example 7 but substituting another 4I-I-s-triazolo[4,3-a][ l ,4]benzodiazepin-4 01 (I), such as 1. 6-(m-bromophenyl)-7-chloro-l-methyl-4H-s triazo1o-[4,3-a][ 1,4]benzodiazepin-4-ol (I). 2. 8-chloro-6-( 3 ,5-diethylphenyl I-ethylAH-striazolo[4,3-a][ 1,4]benzodiazepin-4-ol (I),

7-bromo-9-ethylthio-6-[ m- (propylsulfonyl)phenyl]-4l-I-s-triazolo[4,3-

a] I ,4]benzodiazepin-4-o1 (I),

4. 1-(diethylamino)methyl-6-[o-(trifluoromethyl phenyl]-9-nitro-4H-s-triaz0lo[4,3-a][ I ,4]benzodiazepin-4-ol (l),

5. 8-bromo-6-( 3-chloro-6-fluoropheny1)-7-ethyl- I pyrrolidinomethyl-4H-s-triazolo[4,3-a][ 1,4]benzodiazepin-4-ol (I).

6. 8chlorol dipropylamino)methyl-9-methyl-6-(pethoxyphenyl)-4H-s-triazolo[4,3-a][ I ,4]benzodiazepin-4-ol (I),

7. l-cyanomethyl-8,9-diethyl-6-(m-nitrophenyl)7- propoxy-4I-I-s-triazolo[4,3-a][ I ,4]benzodiazepin 4-0] (I),

8. l-benzyl-8,9-dibromo-6-(p-iodophenyl)-4H-striazolo[4,3-al[ 1,4]benzodiazepin-4-ol (I),

9. 9-trifluoromethyl-8-ethyl-6-(o-isopropylphenyl)- 4H-s-triazolo[4,3-a][ 1,4]benzodiazepin-4-ol (I), I0. l0-acetylamino-6-(2-ethyl-4-fluorophenyl)-7- propyl-4I-I-s-triazolo[4,3-a][ 1,4]benzodiazepin-4- 01 (I), etc., yields, respectively,

l. 6-( m-bromophenyl )-7-chloro-5 ,G-dihydrol methyl-4H-s-triazolo[4,3-a][ 1,4]benzodiazepin- 4-one (IV),

2. 8-chloro-6-(3,5-diethylphenyl)-5,6-dihydro-1- ethyl-4I-I-s-triazolo[ 4,3-a][ 1 ,4]benzodiazepin- 4-one (IV),

3. 7-bromo-5,6-dihydro-9-ethylthio-6-[rn-(propylsulfonyl)phenyl]-4I'I-s-triazolo[4,3-

a][ 1,4]benzodiazepin-4-one (IV), I

4. I'(diethylamino)methyl-S,6-dihydro-6-[o- (trifluoromethyl )phenyl ]-9-nitro-4H-striazolo[4,3-a][ 1,4]benzodiazepin-4-one (IV),

5. 8-bromo-6-(3-chloro-5-fluorophenyl)-5,6

dihydro-7-ethyll -pyrrolidinomethyl-4I-I-striazolo[4,3-a][ 1,4]benzodiazepin-4-one (IV),

6. 8-chloro-5,6-dihydro-1-(dipropylamin0)methyl-9- methyl-G-(p-ethoxyphenyl)-4H-s-triazolo[4,3-

a][ 1,4]benzodiazepin-4-one (IV),

7. l-cyanomethyl-8 ,9-diethyl-5 ,6-dihydro-6-( mnitrophenyl)-7-propoxy-4H-s-triazoloI4,3- a][ I ,4]benzodiazepin-4-one (IV),

8. l-benzyl-8,9-dibromo-5,6-dihydro-6-(piodophenyl)-4H-s-triazolo[4,3- a][ 1,4]benzodiazepin-4-one (IV),

9. 9-trifluoromethyl-5,6-dihydro-8-ethyl-6-(oisopropylphenyl )-4I-I-s-triazolo[4,3 a][ 1,4]benzodiazepin-4-one (IV),

10. l0-acetylamino-6-( 2-ethyl-4-fluorophenyl )-5 ,6-

dihydro-7-propyl-4H-s-triazolo[4,3- a][ 1 ,4]benzodiazepin-4-one (IV), etc.

I claim:

[1. A compound selected from the group consisting of those represented by the formulae:

wherein R is selected from the group consisting of hydrogen, lower alkyl of one through three carbon atoms, phenyl, benzyl, nitromethyl, cyanomethyl, lower alkoxymethyl having an alkoxy moiety of one through three carbon atoms;

in which n is an integer of 1 through 2, R and R" are each selected from the group consisting of hydrogen and alkyl of one through three carbon atoms and when combined is an alkylidene bridge of four through five carbon atoms; R is selected from the group consisting of hydroxy and lower acyloxy', R R;,, R, and R are selected from the group consisting of hydrogen, lower alkyl of one through three carbon atoms, halogen, nitro, cyano, trifluoromethyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, amino, lower alkanoylamino and lower dialkylamino; and a pharmacologically acceptable acid addition salt thereof.]

[2. A compound of Formula I of claim 1 wherein R is methyl, R is hydroxy, R R and R are hydrogen and R is 8-chloro, namely, 8-chloro-l-methyl-6- phenyl-4H-s-triazolo-[4,3-a][ 1 ,4]benzodiazepin-4- L] [3. A compound of Formula I of claim 1 wherein R is methyl, R, is acetoxy, R R and R are hydrogen and R, is 8-chloro, namely, 4-acetoxy-8-chloro-l-methyl-6- phenyl-4H-s-triazolo-[4,3a][ l ,41benzodiazepine] [4. A compound of Formula ll of claim 1 wherein R is methyl, R R and R are hydrogen and R is 8- chloro, namely, 8-chloro-l-methyl-6-phenyl-4H-striazolo[4,3 a][1,4]benzodiazepine S-oxideJ [5. A compound of Formula II] of claim 1 wherein R is methyl, R R and R are hydrogen and R is 10- chloro, namely, l0-chloro-6-methyl-l lb-phenyl- 3H,l lbH-oxazirino-[ 3 ,2-d]-s-triazolo[4 ,3--

a][ 1,4]benzodiazepine] [6. A compound of Formula IV of claim 1 wherein R is methyl, R R and R are hydrogen and R, is 8- chloro, namely, 8-chloro-5,6-dihydro-l-methyl-6- phenyl-4H-s-triazolo[4,3 -a][ l ,4]benzodiazepin- 4'one.]

7. A compound of the formula wherein R is selected from the group consisting of h ydrogen, lower alkyl of I through 3 carbon atoms, phenyl, benzyl, nitromethyl, cyanomethyl, lower alkoxymethyl having an alkoxy moiety of 1 through 3 carbon atoms;

in which n is an integer of I through 2, R and R" are each selected from the group consisting of hydrogen and alkyl of 1 through 3 carbon atoms and when combined is an alkylidene bridge of4 through 5 carbon atoms; R R R and R are selected from the group consisting of hydrogen, lower alkyl of I through 3 carbon atoms, halogen, nitro, cyano, trifluoromethyl, lower alkoxy, lower alkylthio, lower alkyl sulfinyl, lower alkylsulfonyl, amino, lower alkanoyl amino and di-lower alkyl amino; and a pharmacologically acceptable acid addition salt thereof.

8. IO-Chloro-6-methyl-1lb-phenyl-3H,llbl-I- oxazirino[3,2-d]-s-triazolo[4,3-a] 1,4]benzodiazepine.

9. A compound of the formula wherein R is selected from the group consisting of hydrogen, lower alkyl of 1 through 3 carbon atoms, phenyl, benzyl, nitromethyl, cyanomethyl, lower alkoxymethyl having an alkoxy moiety of I through 3 carbon atoms,

(cH2 R in which n is an integer of 1 through 2, R and R" are each selected from the group consisting of hydrogen and alkyl of I through 3 carbon atoms and when combined is an alkylidene bridgeof 4 through 5 carbon atoms, R R R and R are selected from the group consisting of hydrogen, lower alkyl of I through 3 carbon atoms, halogen, nitro, cyano, trtfluoromethyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, amino, lower alkanoylamino and di-lower alkyl amino; and a pharmacologically acceptable acid addition salt thereof.

10. 8- Chloro-5,6-dilz vdrol -methyl-6-phenyl-4H-striazolo{4,3-a] l ,4]benzodiazepine-4-one. 

8. 10-Chloro-6-methyl-11b-phenyl-3H,11bH-oxazirino(3,2-d)-s-triazolo(4,3 -a)(1,4)benzodiazepine.
 10. 8-Chloro-5,6-dihydro-1-methyl-6-phenyl-4H-s-triazolo(4,3 -a)(1,4)benzodiazepine-4-one. 